The present invention is directed to the synthesis of taxol and other tricyclic and tetracyclic taxanes and novel intermediates thereof.
The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has the following structure: 
wherein Ac is acetyl.
The supply of taxol is presently being provided by the bark from Taxus brevifollia (Western Yew). However, taxol is found only in minute quantities in the bark of these slow growing evergreens. Consequently, chemists in recent years have expended their energies in trying to find a viable synthetic route for the preparation of taxol. To date, the results have not been entirely satisfactory.
A semi-synthetic approach to the preparation of taxol has been described by Greene, et al. in JACS 110, 5917 (1988), and involves the use of a congener of taxol, 10-deacetyl baccatin III which has the structure of formula II shown below: 
10-deacetyl baccatin III is more readily available than taxol since it can be obtained from the needles of Taxus baccata. According to the method of Greene et al., 10-deacetyl baccatin III (xe2x80x9c10-DABxe2x80x9d) is converted to taxol by attachment of the C-10 acetyl group and by attachment of the C-13 xcex2-amido ester side chain through the esterification of the C-13 alcohol with a xcex2-amido carboxylic acid unit.
Denis et al. in U.S Pat. No. 4,924,011 disclose another process for preparing derivatives of baccatin III or of 10-deacetylbaccatin III of general formula 
in which Rxe2x80x2 denotes hydrogen or acetyl. As reported, an acid of general formula: 
in which R1 is a hydroxy-protecting group, is condensed with a taxane derivative of general formula: 
in which R2 is an acetyl hydroxy-protecting group and R3 is a hydroxy-protecting group, and the protecting groups R1, R3 and, where appropriate, R2 are then replaced by hydrogen.
Other semisynthetic approaches for the preparation of taxol and for the preparation of other taxanes which possess tumor-inhibiting properties have been reported in recent years, but each of these approaches requires 10-DAB or baccatin III as a starting material. As such, the supply of taxol and other taxane derivatives remains dependent at least to some extent upon the collection of various parts of plants from the remote corners of the world and the extraction of 10-DAB and/or baccatin III therefrom.
Among the objects of the present invention, therefore, is the provision of a process for the synthesis of taxol and other tetracyclic taxanes; the provision of such a process which is highly diastereoselective; the provision of such a process which proceeds in relatively high yield; and the provision of key intermediates and processes for their preparation.
Briefly, therefore, the present invention is directed to a process for the preparation of taxol and other tricyclic and tetracyclic taxanes.
In accordance with one aspect of the present invention, the process comprises reacting a compound having the formula 
with BrMgN(iPr)2, an aldehyde (or ketone), followed by phosgene and an alcohol to form a compound having the formula: 
wherein
R1 is hydrogen or protected hydroxy; R2 is hydrogen or protected hydroxy;
R3 is oxo;
R7b is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or xe2x80x94OCOR36;
R7c and R7d are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R9 is hydrogen, protected hydroxy, or oxo;
R10 is xe2x80x94OP10;
R13 is xe2x80x94OP13;
R36 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
P10 and P13 are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula 
with lithium tetramethylpiperidide to form a compound having the formula: 
wherein
R1 is hydrogen or protected hydroxy;
R7c, is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R9 is hydrogen, protected hydroxy, or oxo; and
P10 and P13 are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula: 
with lithium tetramethylpiperidide and camphosulfonyl oxaziridine to form a compound having the formula: 
wherein R9 is hydrogen, protected hydroxy, or oxo; R7c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P10 and P13 are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula: 
with a hydride reducing agent, preferably Red-Al, to form a compound having the formula: 
wherein R9 is hydrogen, protected hydroxy, or oxo; R7c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; and P10 and P13 are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula: 
with lithium diisopropylamide to form a compound having the formula: 
wherein R is lower alkyl, R1 is hydrogen, protected hydroxy or R1 and R2 together form a carbonate, R2 is hydrogen, protected hydroxy or R1 and R2 together form a carbonate, R9 is hydrogen, protected hydroxy, or oxo; and P10 and P13 are hydroxy protecting groups.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula: 
with DBU to form a compound having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, or together with R1 is a carbonate;
R4a is hydrogen, alkyl, hydroxy, or protected hydroxy, or together with R2 is a carbonate;
R4b is hydroxymethylene;
R5 is xe2x80x94OMs, xe2x80x94OTs or a bromide;
R7a is hydrogen, protected hydroxy, or xe2x80x94OCOR34, or together with R9 is a carbonate;
R9 is hydrogen, oxo, hydroxy, protected hydroxy, or xe2x80x94OCOR33, or together with R7a or R10 is a carbonate;
R10 is hydrogen, oxo, hydroxy, protected hydroxy, or xe2x80x94OCOR29, or together with R9 is a carbonate;
P13 is a hydroxy protecting group;
R29, R30, R31, R33 and R34 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl.
In accordance with another aspect of the present invention, the process comprises reacting a compound having the formula: 
with KOtBu and (PhSeO)2O to form a compound having the formula: 
which rearranges in the presence of additional KOtBu, silica gel, or other acids or bases, or with heat to a compound having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy, or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, protected hydroxy, or xe2x80x94OCOR31, or together with R1 or R4a is a carbonate;
R4a is hydrogen, alkyl, hydroxy, protected hydroxy, or xe2x80x94OCOR27, together with R4b is an oxo, or together with R2, R4b, or R5 is a carbonate;
R4b is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cyano, together with R4a is an oxo, together with R4a or R5 is a carbonate, or together with R5 and the carbons to which they are attached form an oxetane ring;
R5 is hydrogen, protected hydroxy, xe2x80x94OCOR37, together with R4a or R4b is a carbonate, or together with R4b and the carbons to which they are attached form an oxetane ring;
R7a is hydrogen, halogen, protected hydroxy, or xe2x80x94OCOR34;
P13 is a hydroxy protecting group;
R27, R30, R31, R34 and R37 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; and
X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl.
In general, the process of the present invention may be used to prepare taxanes having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy, or xe2x80x94OCOR30;
R2 is hydrogen, hydroxy, xe2x80x94OCOR31, or oxo;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, xe2x80x94OCOR27, or together with R4b forms an oxo, oxirane or methylene;
R4b is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5 and the carbon atoms to which they are attached form an oxetane ring;
R5 is hydrogen, halogen, hydroxy, protected hydroxy, xe2x80x94OCOR37, oxo, or together with R4b and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7a is hydrogen, halogen, hydroxy, protected hydroxy, xe2x80x94OCOR34, oxo, or xe2x80x94OR28;
R9 is hydrogen, hydroxy, protected hydroxy, acyloxy, or oxo;
R10 is hydrogen, xe2x80x94OCOR29, hydroxy, protected hydroxy, or oxo;
R13 is hydroxy, protected hydroxy, MOxe2x80x94 or 
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R28 is a functional group which increases the solubility of the taxane;
R27, R29, R30, R31, R34 and R37 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl;
X1 is xe2x80x94OX6, xe2x80x94SX7, or xe2x80x94NX8X9;
X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X5 is xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10, xe2x80x94CONX8X10, or xe2x80x94SO2X11;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
X10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OX10, or xe2x80x94NX8X14;
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The present invention is additionally directed to an intermediate for use in the preparation of a tricyclic or tetracyclic taxane having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR 30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, or together with R1 is a carbonate;
R3 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR32, or oxo;
R8 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R9 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR33, or together with R10 is a carbonate;
R10 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR29, or together with R9 is a carbonate;
R13 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR35 or MOxe2x80x94;
R29, R30, R31, R32, R33, and R35 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX19, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The present invention is further directed to an intermediate for use in the preparation of a tricyclic or tetracyclic taxane having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, or together with R1 is a carbonate;
R3 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR32, or oxo, or together with R7b is a carbonate;
R7b is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or xe2x80x94OCOR36, or together with R3 or R9 is a carbonate;
R7c and R7d are independently hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R9 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR33, or together with R7b or R10 is a carbonate;
R10 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR29, or together with R9 is a carbonate;
R13 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR35 or MOxe2x80x94;
R29, R30, R31, R32, R33, R35 and R36 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The invention is further directed to an intermediate for use in the preparation of a tricyclic or tetracyclic taxane having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, or together with R1 is a carbonate;
R3 is hydrogen, hydroxy, protected hydroxy, or xe2x80x94OCOR32;
R7b is hydrogen, alkyl, cyano, hydroxy, protected hydroxy, or xe2x80x94OCOR36;
R7c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl;
R9 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR33, or together with R10 is a carbonate;
R10 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR29, or together with R9 is a carbonate;
R13 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR35 or MOxe2x80x94;
R29, R30, R31, R32, R33, R35 and R36 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The present invention is further directed to an intermediate for use in the preparation of a tricyclic or tetracyclic taxane having the formula: 
wherein
R is C1-C8 alkyl,
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, together with R1 is a carbonate, or together with R4 is a carbonate;
R4a is hydrogen, alkyl, hydroxy, protected hydroxy, or xe2x80x94OCOR27, or together with R2 is a carbonate;
R7a is hydrogen, halogen, hydroxy, protected hydroxy, xe2x80x94OR28, xe2x80x94OCOR34, or together with R9 is a carbonate;
R9 is hydrogen, oxo, hydroxy, protected hydroxy, xe2x80x94OR28, or xe2x80x94OCOR33, or together with R7a or R10 is a carbonate;
R10 is hydrogen, oxo, hydroxy, protected hydroxy, xe2x80x94OR28, or xe2x80x94OCOR29, or together with R9 is a carbonate;
R13 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR35 or MOxe2x80x94;
R28 is a functional group which increases the solubility of the taxane derivative;
R27, R29, R30, R31, R33, R34, and R35 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The invention is further directed to an intermediate for use in the preparation of a tricyclic or tetracyclic taxane having the formula: 
wherein
R1 is hydrogen, hydroxy, protected hydroxy or xe2x80x94OCOR30, or together with R2 is a carbonate;
R2 is hydrogen, hydroxy, protected hydroxy, oxo, or xe2x80x94OCOR31, or together with R1 or R4a is a carbonate;
R4a is hydrogen, alkyl, hydroxy, protected hydroxy, or xe2x80x94OCOR27, together with R4b is an oxo, or together with R2, R4b, or R5 is a carbonate;
R4b is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or cyano, together with R4a is an oxo, together with R4a or R5 is a carbonate, or together with R5 and the carbons to which they are attached form an oxetane ring;
R5 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR37, oxo, together with R4a or R4b is a carbonate, or together with R4b and the carbons to which they are attached form an oxetane ring;
R7a is hydrogen, halogen, hydroxy, protected hydroxy, xe2x80x94OR28, or xe2x80x94OCOR34, or together with R9 is a carbonate;
R9 is hydrogen, oxo, hydroxy, protected hydroxy, xe2x80x94OR28, or xe2x80x94OCOR33, or together with R7a or R10 is a carbonate;
R10 is hydrogen, oxo, hydroxy, protected hydroxy, xe2x80x94OR28, or xe2x80x94OCOR29, or together with R9 is a carbonate;
R13 is hydrogen, hydroxy, protected hydroxy, xe2x80x94OCOR35, MOxe2x80x94 or 
R28 is a functional group which increases the solubility of the taxane derivative;
R27, R28, R30, R31, R33, R34, R35 and R37 are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, xe2x80x94NX8X10, xe2x80x94SX10, monocyclic aryl or monocyclic heteroaryl;
X1 is xe2x80x94OX6, xe2x80x94SX7, or xe2x80x94NX8X9;
X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X5 is xe2x80x94COX10, xe2x80x94COOX10, xe2x80x94COSX10, xe2x80x94CONX8X10, or xe2x80x94SO2X11;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X9 is an amino protecting group;
X10 is alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, xe2x80x94OX10, or xe2x80x94NX8X14;
X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and
M comprises ammonium or is a metal.
The present invention is additionally directed to compounds having the formulae 
wherein
R is lower alkyl,
T4 is hydroxy or protected hydroxy,
T4a and T4b are independently alkoxy, alkoxycarbonyloxy, acyloxy, sulfonyloxy, hydroxy, or protected hydroxy, or together form a carbonate,
T5 is alkoxy, alkoxycarbonyloxy, acyloxy, sulfonyloxy, hydroxy, or protected hydroxy,
P5, P7, P10 and P13 are hydroxy protecting groups, and
R2, R4a, R7a, R10a, and R13 are as previously defined. These compounds are key intermediates in the synthesis of taxol and other taxanes. The present invention is also directed to processes for the preparation of these key intermediates.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
As used herein xe2x80x9cArxe2x80x9d means aryl; xe2x80x9cPhxe2x80x9d means phenyl; xe2x80x9cMexe2x80x9d means methyl; xe2x80x9cEtxe2x80x9d means ethyl; xe2x80x9ciPrxe2x80x9d means isopropyl; xe2x80x9ctBuxe2x80x9d and xe2x80x9ct-Buxe2x80x9d means tert-butyl; xe2x80x9cRxe2x80x9d means lower alkyl unless otherwise defined; xe2x80x9cAcxe2x80x9d means acetyl; xe2x80x9cpyxe2x80x9d means pyridine; xe2x80x9cTESxe2x80x9d means triethylsilyl; xe2x80x9cTMSxe2x80x9d means trimethylsilyl; xe2x80x9cTBSxe2x80x9d means Me2t-BuSi-; xe2x80x9cTfxe2x80x9d means xe2x80x94SO2CF3; xe2x80x9cBMDAxe2x80x9d means BrMgNiPr2; xe2x80x9cSwernxe2x80x9d means (COCl)2, Et3N; xe2x80x9cLTMPxe2x80x9d means lithium tetramethylpiperidide; xe2x80x9cMOPxe2x80x9d means 2-methoxy-2-propyl; xe2x80x9cBOMxe2x80x9d means benzyloxymethyl; xe2x80x9cLDAxe2x80x9d means lithium diisopropylamide; xe2x80x9cLAHxe2x80x9d means lithium aluminum hydride; xe2x80x9cRed-Alxe2x80x9d means sodium bis(2-methoxyethoxy) aluminum hydride; xe2x80x9cMsxe2x80x9d means CH3SO2xe2x80x94; xe2x80x9cTASFxe2x80x9d means tris(diethylamino)sulfonium-difluorotrimethylsilicate; xe2x80x9cTsxe2x80x9d means toluenesulfonyl; xe2x80x9cTBAFxe2x80x9d means tetrabutyl ammonium fluoride; xe2x80x9cTPAPxe2x80x9d means tetrapropyl-ammonium perruthenate; xe2x80x9cDBUxe2x80x9d means diazabicycloundecane; xe2x80x9cDMAPxe2x80x9d means p-dimethylamino pyridine; xe2x80x9cLHMDSxe2x80x9d means lithium hexamethyldisilazide; xe2x80x9cDMFxe2x80x9d means dimethylformamide; xe2x80x9cAIBNxe2x80x9d means azo-(bis)-isobutyronitrile; xe2x80x9c10-DABxe2x80x9d means 10-desacetylbaccatin III; xe2x80x9cFARxe2x80x9d means 2-chloro-1,1,2-trifluorotriethylamine; xe2x80x9cmCPBAxe2x80x9d means metachloroperbenzoic acid; xe2x80x9cDDQxe2x80x9d means dicyanodichloroquinone; xe2x80x9csulfhydryl protecting groupxe2x80x9d includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; xe2x80x9camine protecting groupxe2x80x9d includes, but is not limited to, carbamates, for example, 2,2,2,-trichloroethylcarbamate or tertbutylcarbamate; xe2x80x9cprotected hydroxyxe2x80x9d means xe2x80x94OP wherein P is a hydroxy protecting group; and xe2x80x9chydroxy protecting groupxe2x80x9d includes, but is not limited to, acetals having two to ten carbons, ketals having two to ten carbons, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoro-acetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. They may be hydrocarbon or heterosubstituted with the various substituents defined herein, including heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.
The alkenyl groups described herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. They may be hydrocarbon or heterosubstituted with the various substituents defined herein, including alkyl, heteroalkyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.
The alkynyl groups described herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. They may be hydrocarbon or heterosubstituted with the various substituents defined herein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, and heterosubstituted heteroaryl.
The aryl moieties described herein contain from 6 to 15 carbon atoms and include phenyl. They may be hydrocarbon or heterosubstituted with the various substituents defined herein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, heteroaryl, and heterosubstituted heteroaryl. Phenyl is the more preferred aryl.
The heteroaryl moieties described herein contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. They may be hydrocarbon or heterosubstituted with the various substituents defined herein, including alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, and heterosubstituted heteroaryl.
The acyl moieties described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The alkoxycarbonyloxy moieties described herein comprise lower alkyl, alkenyl, alkynyl or aryl groups.
The hydrocarbon substituents described herein may be alkyl, alkenyl, alkynyl, or aryl, and the heterosubstituents of the heterosubstituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl moieties described herein contain nitrogen, oxygen, sulfur, halogens and/or one to six carbons, and include lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, and nitro, heteroaryl such as furyl or thienyl, alkanoxy, hydroxy, protected hydroxy, acyl, acyloxy, nitro, amino, and amido.
An exemplary synthesis of baccatin III or 10-DAB is depicted hereinbelow in Reaction Scheme A. The starting material, diol 2, can be prepared from patchino (commonly known as B-patchouline epoxide) which is commercially available. The patchino is first reacted with an organo-metallic, such as lithium t-butyl followed by oxidation with an organic peroxide, such as t-butylperoxide in the presence of titanium tetraisopropoxide to form a tertiary alcohol. The tertiary alcohol is then reacted with a Lewis acid, such as boron trifluoride at low temperature, in the range from 40xc2x0 C. to xe2x88x92100xc2x0 C.; in the presence of an acid, such as trifluoromethane sulfonic acid. A graphical depiction of this reaction scheme along with an experimental write-up for the preparation of diol 2 can be found in U.S. Pat. No. 4,876,399. 
In Reaction Scheme A, P5 is TMS, P7 is MOP or BOM, P10 is TES, P13 is TBS, and R is ethyl in compounds 6 and 7, methyl in compounds 15, 16, and 17, Ms in compounds 24aa and 26a, and Ts in compound 26aa. It should be understood, however, that P5, P7, P10, and P13 may be other hydroxy protecting groups and R may comprise other lower alkyl substituents in compounds 6, 7, 15, 16 and 17.
Reaction Scheme A may be varied between compounds 18 and 29 as set forth below in Reaction Scheme Axe2x80x2, with the reactions leading to compound 18 and following compound 29 being as set forth in Reaction Scheme A. 
In Reaction Scheme Axe2x80x2, P5 is TMS or Ac, P7 is MOP or BOM, P10 is TES, P13 is TBS and P520 is acetal or ketal, preferably acetonide. It should be understood, however, that P5, P7, P10, and P13 and P520 may be other hydroxy protecting groups.
In general, tricyclic and tetracyclic taxanes bearing C13 side chains may be obtained by reacting a xcex2-lactam with alkoxides having the taxane tricyclic or tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a xcex2-amido ester substituent at C-13. The xcex2-lactams have the following structural formula: 
wherein X1-X5 are as defined above. The alkoxides having the tricyclic or tetracyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula: 
wherein R1, R2, R4a, R4b, R5, R6, R6a, R7a, R9, R10, R14, and R14a are as previously defined, R13 is xe2x80x94OM and M comprises ammonium or is a metal optionally selected from Group IA, IIA, transition (including lanthanides and actinides), IIB, IIIA IVA, VA, or VIA metals (CAS version). If M comprises ammonium, it is preferably tetraalkylammonium and the alkyl component of the tetraalkylanmonium substituent is preferably C1xe2x80x94C10 alkyl such as methyl or butyl. Most preferably, the alkoxide has the tetracyclic taxane nucleus and corresponds to the structural formula: 
wherein M, R2, R4a, R7a, R9, and R10 are as previously defined.
As set forth in Reaction Scheme A, taxol may be prepared by converting 7-protected Baccatin III 35 to the corresponding alkoxide and reacting the alkoxide with a xcex2-lactam in which X1 is protected hydroxy, X3 is phenyl and X5 is benzoyl. Protecting groups such as 2-methoxypropyl (xe2x80x9cMOPxe2x80x9d), 1-ethoxyethyl (xe2x80x9cEExe2x80x9d) are preferred, but a variety of other standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups may be used. Taxanes having alternative side chain substituents may be prepared through the use of xcex2-lactams which comprise the alternative substituents.
Taxanes having alternative C9 substituents may be prepared by selectively reducing the C9 keto substituent of taxol, 10-DAB, Baccatin III or one of the other intermediates disclosed herein to yield the corresponding C9 xcex2-hydroxy derivative. The reducing agent is preferably a borohydride and, most preferably, tetrabutylammoniumboro-hydride (Bu4NBH4) or triacetoxyborohydride.
As illustrated in Reaction Scheme 1, the reaction of baccatin III with Bu4NBH4 in methylene chloride yields 9-desoxo-9xcex2-hydroxybaccatin III 5. After the C7 hydroxy group is protected with the triethylsilyl protecting group, for example, a suitable side chain may be attached to 7-protected-9xcex2-hydroxy derivative 6 as elsewhere described herein. Removal of the remaining protecting groups thus yields 9xcex2-hydroxy-desoxo taxol or other 9xcex2-hydroxytetracylic taxane having a C13 side chain. 
Alternatively, the C13 hydroxy group of 7-protected-9xcex2-hydroxy derivative 6 may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to the C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of the various substituents of the taxane. For example, reaction of 7,13-protected-9xcex2-hydroxy derivative 7 with KH causes the acetate group to migrate from C10 to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8. Protection of the C10 hydroxy group of 10-desacetyl derivative 8 with triethylsilyl yields derivative 9. Selective removal of the C13 hydroxy protecting group from derivative 9 yields derivative 10 to which a suitable side chain may be attached as described above. 
As shown in Reaction Scheme 3, 10-oxo derivative 11 can be provided by oxidation of 10-desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-acetoxy-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain. Alternatively, the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain. 
Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13. The C7 and C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can be attached as described above or, alternatively, after further modification of the tetracylic substituents. 
Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10-DAB as a starting material as illustrated in Reaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent. Selective reduction of the C9 keto substituent of derivative 16 yields 9xcex2-hydroxy derivative 17 to which a C13 side chain may be attached. Alternatively, the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above. 
Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine. Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as set forth in Reaction Schemes 6-10. To simplify the description, 10-DAB is used as the starting material. It should be understood, however, that baccatin III derivatives or analogs may be produced using the same series of reactions (except for the protection of the C10 hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material. 9-desoxo derivatives of the baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can then be prepared by reducing the C9 keto substituent of these analogs and carrying out the other reactions described above.
In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18 with lithium aluminum hydride. Triol 18 is then converted to the corresponding C4 ester using Cl2CO in pyridine followed by a nucleophilic agent (e.g., Grignard reagents or alkyllithium reagents). 
Deprotonation of triol 18 with LDA followed by introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
Triol 18 can also readily be converted to the 1,2 carbonate 19. Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 6. 
As set forth in Reaction Scheme 9, other C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or Grignard reagents to provide 10-DAB derivatives having new substituents at C2. 
Alternatively, baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using Cl2CO and pyridine, and carbonate 25 is acylated at C10 with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10. 
10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives of 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium diiodide. Reaction between the tetracyclic taxane having a C10 leaving group and samarium duiodide may be carried out at 0xc2x0 C. in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group; C13 side chains and other substituents on the tetracyclic nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9xcex2-hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 11, 12 and 12a. 
As shown in Reaction Scheme 12, Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride.
Taxanes having C7 acyloxy-substituents can be prepared as set forth in Reaction Scheme 12a, 7,13-protected 10-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the C13 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a P-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
As shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetrafluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone. 
The subprocesses of Reaction scheme A can be applied at various stages. For example, the process for the conversion of compound 30 to compound 33 can be applied to any intermediate having a hydroxyl group at C-10 and two hydrogens at C-9, e.g., the process for introducing C9 and C10 carbonyl and hydroxyl groups can be applied to suitably protected intermediates 4 through 29.
Likewise, the process for introduction of C1 and C2 oxygen-containing functional groups (conversion of 6 to 13 in Reaction Scheme A) can be applied to any intermediate having a C3 carbonyl group.
Similarly, the process for introducing C2 and C4 acyl groups as exemplified in Reaction Schemes 6 through 10 can be applied to any intermediate having a C1, C2 carbonate.
Also, the process for forming the oxetane ring, as exemplified in the conversion of 24a to 27a in Reaction Scheme A, can be applied to a variety of intermediates having a C4 carbonyl group.
The aldol process exemplified in the conversion of 5 to 6 in Reaction Scheme A can be applied to any suitably protected intermediate having a C3 carbonyl group and a xcex58a hydrogen. A variety of ketones or aldehydes can be used as a reactant in this process.
Formation of a cyclic carbonate from any 1,2 or 1,3 diol subunit in any intermediate can be carried out by using phosgene as a reactant. Carbonyl groups can be reduced by hydride reagents or metallic species to the corresponding alcohols. Alcohols can be oxidized using a variety of oxidizing agents as exemplified in the Reaction Schemes, to the corresponding carbonyl groups.
The compounds disclosed in this application have several asymmetric carbons and may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention. More specifically, the present invention includes the enantiomers, diasteriomers, racemic mixtures, and other mixtures of the compounds disclosed herein.